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The Goal

The Goal. Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler et al., (2005). The Problem.

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The Goal

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  1. The Goal Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Hasler et al., (2005)

  2. The Problem Understanding the etiology of disease X requires a genetic diathesis interacting with environmental, epigenetic and stochastic components. Underlying genetic diatheses and environmental, epigenetic and stochastic mechanisms have remained mostly uncharacterized. Hasler et al., (2005)

  3. Source(s) of the Problem Heterogeneity of phenotype (DSM Category) Diagnostic errors Environmental effects Multiple genes with small effects Gene X Gene interactions Gene X Environment interactions Epigenetic factors

  4. How Bad Is The Problem? p (disease|gene) • Odds ratio = p (disease|no-gene)

  5. Odd’s Ratio Kendler, 2005

  6. Huntington’s X Y One-to-one relationship

  7. Anxiety • A V • B W • X Y • C Z Many-to-many relationship

  8. Types of Markers (Need not be Biological) • Episode – associated only with active symptoms • May or may not be genetic • Not a genetic marker – would miss compensated or ‘at-risk’ • May predict treatment outcome in specific subgroup, etc. • Vulnerability – prone to illness, but not part of pathological genotype (black skin & sickle cell) • Genetic – associated with the pathological gene • Linkage – non-allelic genes in close proximity are linked to disorder • Direct manifestation of genetic diasthesis • These are endophenotypes Iacono, 1988

  9. Anxiety • A V • B W • X Y • C Z Many-to-many relationship

  10. Anxiety • A V • B W • X Y • C Z Many-to-many relationship

  11. Endophenotypes ?

  12. Endophenotypes ?

  13. Endophenotypes ?

  14. Be Careful What You Ask For • Flint & Munafo, 2007 • COMT polymorphism & schizophrenia • COMT regulates dopamine • Odds ratio = 1.13 • How about endophenotypes? • Move closer to the genes • Genes should account for more variance • Neuropsychological dysfunction associated with prefrontal cortex

  15. This Is What You May Get • Wisconsin Card Sorting Task • Recognized measure of prefrontal function • Effect size of association = 0.5% of variance

  16. This Is What You May Get • Wisconsin Card Sorting Task • Recognized measure of prefrontal function • Effect size of association = 0.5% of variance • N-Back task • Effect size was the same (0.5% of variance)

  17. This Is What You May Get • Wisconsin Card Sorting Task • Recognized measure of prefrontal function • Effect size of association = 0.5% of variance • N-Back task • Effect size was the same (0.5% of variance) • P300 • Effect size was even worse (0.01% of the variance)

  18. Schizophrenia • A V • B W • X Y • C Z

  19. Conclusions • Odds ratios in psychiatric disorders are very low • Endophenotype strategy is very hot & plausible -- at least theoretically • Identifying a good endophenotype is difficult • Pay attention to the criteria • Don’t drop bomblets – do the work • Current status • Some say only success to date is in schizophrenia • But Flint & Munafo is discomfiting • Have fun – but “Be careful out there”.

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